Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and frequently becomes resistant to drug therapy, presenting an enormous social and medical problem. However, the cellular and synaptic mechanisms underlying epilepsy in the temporal lobe are poorly understood. There is substantial evidence from both humans and animal models indicating that the medial entorhinal cortex (MEC) plays critical roles in the generation and maintenance of TLE. Recently, we discovered that a major class of perisomatically projecting basket cells selectively innervate principal cells in layer II of the MEC that project outside the hippocampus, but avoid the neighboring cells that give rise to the perforant pathway to the dentate gyrus. Here we propose to test the hypothesis that there is a significant disruption of the normally highly specialized, local GABAergic control of entorhinal cortical output in TLE, and that the compromised GABAergic inhibition constitutes a key mechanism underlying hyperexcitability and spontaneous seizures in the entorhino- hippocampal network. The hypothesis will be tested in the repeated low dose kainate model of TLE during the chronic epilepsy phase, and the assessment will be carried out with paired recording electrophysiological and immunocytochemical methods, complemented by data-driven, large-scale computational modeling approaches. The experiments of this proposal are designed to specifically target cellular-synaptic mechanisms underlying TLE. It is anticipated that defining the functional consequences of experimental TLE on neurons in the MEC will help the future development of novel anti-epileptic treatment strategies. PUBLIC HEALTH RELEVANCE: Many patients with temporal lobe epilepsy have repeated spontaneous seizures that cannot be controlled with existing drug therapies. Spontaneous seizures may be caused by persistently compromised inhibitory circuits that emerge after precipitating insults. The project will determine whether aberrant inhibitory regulation of the entorhino-hippocampal circuits contributes to the generation of seizures.